3rd April 2024

Genetic conditions affecting parathyroid glands

MEN syndromes

Multiple endocrine neoplasia (MEN) syndromes are a rare group of disorders characterised by an inherited predisposition to benign or malignant neoplasms of the endocrine system with characteristic organ involvement. 

Pathophysiology 

MEN syndromes are a group of autosomal dominant disorders divided into ‘types’ by clinical characteristics. MEN1 affects 1-3 in 100,000 and is due to a defect in the MEN1 gene, whilst MEN2 has been reported in approximately 1000 families worldwide and is caused by a mutated RET proto-oncogene. Based on clinical characteristics, MEN2 can be further subdivided into MEN2A and MEN2B subtypes (see Table 1). Other genetic conditions affecting the parathyroid gland include pseudohypoparathyroidism.

Table 1: characteristics of different MEN syndromes. 

*This is the most common presenting feature of individuals with MEN1.

Tumours form in distinctive organ systems and may be functioning or non-functioning; hypersecretion of hormones from functioning tumours leads to specific symptoms dependent on tumour type. Individuals with MEN1 can present with hypercalcaemia caused by hyperparathyroidism. 40-70% of patients with MEN1 have pancreatic neuroendocrine tumours; ranging from insulinomas, which present with hypoglycaemia, VIPomas causing severe, watery diarrhoea, to gastrinomas, (Zollinger-Ellison syndrome). Zollinger-Ellison syndrome is the most common cause of symptomatic disease in patients with pancreatic tumours.

Management

Early prophylactic thyroidectomy in patients diagnosed genetically with MEN2 in childhood may be indicated, given that most patients will ultimately develop MTC. Otherwise, treatment centres around surgical management of tumours and medical management of symptomatology. Routine monitoring of known carriers begins in childhood and should take place every few years to reduce associated morbidity and mortality.

DiGeorge syndrome

Di George syndrome is an autosomal dominant syndrome caused by a deletion in chromosome 22 (22q11.2). Nearly two-thirds of children with Di George syndrome present with hypocalcaemia in the neonatal period, characterised by jitteriness, tetany, or seizures. This is caused by underdevelopment of the parathyroid glands. Patients may also be identified during the neonatal period due to congenital heart defects, such as tetralogy of Fallot, atrial or ventricular septal defects or truncus arteriosus. Children classically present with a triad of cardiac anomalies, hypoplastic thymus and hypocalcaemia.

However, some children do not present with such overt symptoms and, therefore, may be diagnosed later in life due to delayed development, failure to thrive or frequent infections. An absent or hypoplastic thymus gland, resulting in T cell deficiency, may lead to recurrent sinopulmonary infections or viral infections. Developmental delay occurs in most patients with DGS, with many children experiencing speech delay, in part due to palatal abnormalities such as cleft palates.

Investigations

Di George syndrome is diagnosed based on reduced CD3+ T cells, together with characteristic clinical findings (as described above) or detected deletion of chromosome 22q11.2.

Management 

Acute management in neonates centres around management of hypocalcaemia and surgical correction of significant congenital cardiac defects. Feeding and swallowing problems due to palatal or gastrointestinal defects may be critical issues in the first few days of life. Those with complete athymia are unlikely to survive beyond the first few years of life.

Autoimmune polyendocrinopathy syndrome

Type 1 autoimmune polyendocrinopathy syndrome, also known as ‘autoimmune polyglandular syndrome’, is a rare autosomal recessive condition associated with autoimmune adrenalitis (Addison’s disease), chronic mucocutaneous candidiasis and primary hypoparathyroidism. There is an increased prevalence amongst people from Finland, Sardinia and Iranian Jews. 

Type 2 autoimmune polyendocrinopathy syndrome, also known as Schmidt’s disease, is more prevalent and has several modes of inheritance, including autosomal recessive, polygenic and autosomal dominant. This syndrome encompasses Addison’s disease, autoimmune thyroid disease, and Type 1 diabetes mellitus. Adrenal insufficiency is the initial presentation in around 50% of patients.

References 

• Gorrigan, R., Druce, M. (2021) Multiple endocrine neoplasia syndromes.  BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/866
• Lips, C. (2021) Approach to therapy in multiple endocrine neoplasia type 2. UpToDate [Online] https://www.uptodate.com/contents/approach-to-therapy-in-multiple-endocrine-neoplasia-type-2
• National Organisation for Rare Disorders (NORD). Autoimmune Polyglandular Syndrome Type 1. Rare Disease Database [Online] https://rarediseases.org/rare-diseases/autoimmune-polyglandular-syndrome-type-1/
• BMJ Best Practice (2020) DiGeorge Syndrome. BMJ Best Practice [Online] https://bestpractice.bmj.com/topics/en-gb/947